Cancer arises from cells that escape normal growth regulation through mutations that activate growth-promoting protooncogenes and inactivate tumor suppressor genes. Most often, these genetic alterations are somatic events, but rare individuals are born with heritable, germline mutations of tumor-related genes that make them extremely prone to cancer. Analysis of hereditary cancer predisposition syndromes has been critically important in delineating the role of tumor suppressor genes. Basal cell carcinomas of the skin (BCCs) are the most common malignancies in humans, accounting for approximately one third of all cancers in the U.S. There are slow growing tumors that rarely metastasize, but which can cause significant morbidity and occasional mortality from local invasion. Environmental mutagens, such as ultraviolet and ionizing radiation, are strong risk factors; but little is known about the specific genetic alterations involved in basal cell carcinogenesis. Occasionally these neoplasms arise in an hereditary setting, most commonly in association with Gorlin syndrome. This autosomal dominant disorder is characterized by multiple BCCs, ovarian fibromas, medulloblastomas, meningiomas, fibrosarcomas, and widespread developmental anomalies. In preliminary studies, we showed that the Gorlin syndrome gene maps to chromosome 9q22.3-31 and is deleted in nearly all hereditary and sporadic BCCs. Presumably the gene is a novel tumor suppressor with a critically important role in both carcinogenesis and embryogenesis. Analyzing the function of this gene will help delineate the molecular basis for neoplasia in a variety of solid tumors and, in addition, the role of tumor suppressors in normal development. The purpose of this study is to refine the map location of the gene and to isolate it using positional cloning techniques. A 9q22.3-31 microdissected library will be screened for new STRs, and the map location of the gene will be refined by tumor deletion and linkage studies. Existing YAC contigs that have been constructed by random L1 fingerprinting of the CEPH large-insert library will be tested for the presence of markers in the Gorlin syndrome region and will be further analyzed and extended by content mapping with the new STRs. Simultaneously pools of single copy clones from the microdissected library will be used to directly screen cDNA libraries from tissues in which the gene is likely to be expressed. Those cDNAs that lie in the region of the YAC contig between the closest flanking markers will be analyzed for expression in normal skin cells versus basal cell carcinomas and for mutations in Gorlin syndrome patients. If none of these candidates proves to be the Gorlin syndrome gene, direct cDNA selection from YACs will be used as a complementary and more comprehensive method of identifying additional candidates.